Gliomas are among the most deadly adult cancers; clinical researchers have made few gains in treatment success in the past 30 years. In addition, there is little understanding about the causes of glioma apart from the role of ionizing radiation and a small number of constitutive genetic polymorphisms. An additional recent array of findings in gliomas is related to the role of immune factors: when compared to healthy controls glioma patients report fewer allergies and lower frequencies of varicella-virus-related diseases, and have altered levels of allergy-related IgE and cytokines. The brain has very strong immunomodulatory properties, and inflammation-inducing conditions may damage the brain due to its confined environment. The immune privileged status of the brain means that tumor immunosurveillance mechanisms in the CNS are poorly understood; however, pathogenic viruses with tropism and access to the CNS provide clues to guide research on the role of immune response in CNS malignancies. Varicella Virus (VZV) is a neurotropic virus, and it is hypothesized that an immune response against the virus may facilitate immunosurveillance of brain tumors. To explore this premise, we will investigate the role of specific VZV antigens in elucidating antibody responses in glioma etiology (using pre-diagnostic sera) and in glioma survival (using post-diagnostic sera). Pre- diagnostic specimens are from participants nested within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO, N = 129 cases, and 516 controls), and post-diagnostic are from cases in the San Francisco Bay Area Adult Glioma Study (UCSF AGS, N = 1000 glioma cases with complete treatment and tumor data). We will test for specific anti-VZV response against all 69 proteins that comprise the VZV genome to compare identities and intensities of the antigenic repertoire between glioma cases and controls. We will characterize this antigen response by assessing case-control differences between each individual VZV antigen and case status both before diagnosis of glioma (PLCO) and in glioma survival (UCSF AGS). We will also construct multi-VZV-antigen profiles using multivariable analytic techniques including random forests and partDSA. For the top 4 informative antigens, we will further characterize antigenic specificity by performing a complete linear epitope mapping of those proteins. We will also assess variability in these anti-VZV responses over time using PLCO pre-diagnostic cases (N = 39) and controls (N = 78) for whom 5 serially collected (at 1 year intervals) blood draw sera are available. Anti-VZV responses at the protein and peptide level will provide clues to glioma etiology and possibly individual antigens that cross-react with glioma antigens, providing an enhanced understanding of immune response in gliomagenesis and its clinical relevance.